Heparin and heparin-like molecules have been proposed as therapeutic agents in the atherosclerotic process (Engelberg H. Pharmacol Rev. 1996; 48: 327-351). Besides their well-known anticoagulant action, these molecules regulate leukocyte-blood vessel interactions and infiltration of monocytes/macrophages. The accumulation of macrophage-derived foam cells in atherosclerotic plaques may influence vascular remodeling and plaque rupture, processes implicated in unstable angina and acute myocardial infarction.
The prevalence of chronic and end-stage kidney disease increases with age. According to the Fourth US National Health and Nutrition Examination Survey (NHANES IV, 1999-2004), 23.8% of individuals over 60 years of age and 37.8% of individuals over 70 years of age had a moderate to severe decline of renal function. Reduced renal function in aging could be a significant health issue because it is a known risk factor for kidney failure and cardiovascular disease. The cause of declining renal function in some aging persons is not clear. A process of natural biological aging may play an important role since 13% of older individuals had reduced renal function in the absence of obvious disease such as diabetes and hypertension. Excessive oxidative stress (OS) is critically involved in the overall aging process. There is a strong correlation between renal function and the levels of OS in aging. Additionally, the levels of OS are increased in the kidneys of old animals. Interventions that reduce OS, i.e., caloric restriction and genetic manipulations to overexpress antioxidants, prolong life span and prevent aging related pathologic changes in kidney of animals. Thus, OS may also play an essential role in kidney aging. The presence of intervening disease such as diabetes may accelerate kidney aging process because of the addition of hyperglycemia-induced OS. Hyperglycemia stimulates mitochondrial reactive oxygen species (ROS) generation and increases the formation of advanced glycation end-products (AGEs) intracellularly and extracellularly. Since AGEs also promote OS, a cycle of AGE formation and ROS generation may ensue.
In addition to a close association with elevated OS, the reduction of renal function in aging is also strongly correlated with a state of chronic inflammation, characterized by increased serum levels of tumor necrosis factor α (TNF-α) and its soluble receptors. Since inflammation is a key component of all forms of progressive chronic kidney diseases including diabetic nephropathy, inflammation may be another important contributor to increased renal lesions in aging mice after the induction of diabetes.